Historically, IgA nephropathy (IgAN) was managed using supportive care, with a suggested 6 months of immunosuppressive therapy considered for patients at high risk of progressive kidney function decline (proteinuria, >0.75-1 g/d) despite ≥90 days of optimized supportive care. The evolving treatment landscape includes agents that target immunologic aspects of IgAN or better preserve kidney function, or both. Recent approvals include Nefecon, sparsentan, iptacopan, atrasentan, and sibeprenlimab. Nefecon, a targeted-release formulation of budesonide, is the only US Food and Drug Administration and European Medicines Agency fully approved agent that is designed to target the primary source of IgAN: galactose-deficient IgA1 production in the gut mucosa. Phase 3 data showed that Nefecon slowed estimated glomerular filtration rate decline and decreased proteinuria versus placebo, with an acceptable safety profile. Sparsentan, a fully US Food and Drug Administration- and European Medicines Agency-approved dual endothelin A/angiotensin II receptor antagonist, affects the generic responses to IgAN-induced nephron loss, potentially including glomerular inflammation and fibrosis. Sparsentan demonstrated a significant reduction in proteinuria and estimated glomerular filtration rate decline compared with irbesartan. Iptacopan inhibits complement factor B and has received accelerated US Food and Drug Administration approval. Interim phase 3 study data have shown that iptacopan significantly reduces proteinuria when compared with placebo. The endothelin A receptor antagonist atrasentan and A proliferation binding ligand inhibitor sibeprenlimab have also received accelerated US Food and Drug Administration approval, based on interim phase 3 results showing significant proteinuria reduction versus placebo in patients with IgAN. This expanded clinical armamentarium offers clinicians and patients greater choice and improved disease control in IgAN management.
Increased understanding of the pathogenesis of IgA nephropathy (IgAN) has led to the development of new investigational agents tailored to this disease. The identification of surrogate markers of early treatment benefit has facilitated regulatory approval of these novel therapies. The surge in available data from several completed trials has prompted the recent revision of the Kidney Disease: Improving Global Outcomes guidelines for IgAN. Two agents have been fully approved for use in patients with IgAN in some regions: Nefecon, an oral targeted-release formulation of budesonide, and sparsentan, a dual endothelin A and angiotensin II receptor antagonist. Iptacopan and atrasentan are conditionally approved on the basis of proteinuria data; full approval will be evaluated once data on kidney function are available. With the potential future expansion of the IgAN treatment armamentarium, a dual approach to IgAN management is highly likely, addressing the overproduction of galactose-deficient IgA1 and downstream consequences of deposition of nephritogenic immune complexes, as well as considering supportive strategies targeting common non-disease-specific ongoing nephron loss. Combination therapies with different classes of drugs will likely become the new standard of care for chronic kidney disease as they target distinct pathogenic mechanisms or "hits" (namely, hemodynamic, immune, galactose-deficient IgA1-generating, inflammatory, and fibrotic processes involved in IgAN and chronic kidney disease progression). To improve personalized care for patients with IgAN, further research is needed to identify and validate noninvasive biomarkers for diagnosis, prognosis, treatment selection, and monitoring response.
IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Its incidence and prevalence vary widely, with estimates of annual incidence ranging from 0.06 to 10.5 per 100,000 per year in adults and children. IgAN represents an important cause of progressive kidney disease, leading to kidney failure in a large proportion of patients, and is associated with a wide spectrum of clinical symptoms, which negatively impact quality of life. Although the consequences of IgAN manifest in the kidney, multiple lines of evidence support a major role for the gut in the pathogenesis of IgAN, including genome-wide association studies that identify risk loci for IgAN that encode genes related to mucosal immunity, maintenance of the intestinal epithelial barrier, and inflammatory bowel disease. Further insights into the underlying disease pathogenesis have led to the development of a multihit model comprising 4 sequential "hits": (i) increased levels of galactose-deficient IgA1 in the systemic circulation, (ii) followed by binding of specific autoantibodies directed against galactose-deficient IgA1, which (iii) form pathogenic IgA-containing immune complexes that (iv) deposit within the glomerular mesangium of the kidney, triggering inflammation, damage, and progressive decline in kidney function. The purpose of this article is to provide an overview of IgAN, examining its epidemiology and clinical features, and the mechanisms underlying its pathophysiology.
IgA nephropathy (IgAN) requires effective long-term management to avoid kidney failure. Proteinuria and reductions in estimated glomerular filtration rate are important clinical markers of progression, and they are established surrogate efficacy outcomes in clinical trials of new and emerging IgAN therapies. Despite optimized supportive care (including lifestyle modification and renin-angiotensin system inhibition) as a mainstay of IgAN management, many patients will still develop kidney failure, and the concept of "disease modification" refers to interventions that prevent irreversible kidney damage. Disease-modifying therapies may include IgAN-specific and anti-inflammatory strategies, whereas supportive care encompasses interventions that address generic mechanisms of nephron loss and interstitial injury that lead to chronic kidney disease. Targeted therapies, such as Nefecon (targeted-release formulation budesonide) and iptacopan, which address the immune-mediated pathogenic triggers of nephron loss, are important additions. Lifestyle modification, renin-angiotensin system inhibition, sodium-glucose cotransporter-2 inhibitors, and newer agents, such as sparsentan and atrasentan, are also available to manage the generic responses to IgAN-induced nephron loss common to many forms of proteinuric chronic kidney disease. As our understanding of the pathogenic mechanisms underlying disease progression in IgAN has expanded, so has the recognition that IgAN-specific, targeted immunomodulatory therapies are needed, and that these can be used in combination with other agents addressing the more generic causes of nephron loss. These approaches together can help to modify the course of the disease in patients and avoid progression to kidney failure.
IgA nephropathy is the most prevalent glomerular disease worldwide. To date, a percutaneous kidney biopsy is needed for diagnosis and assessment of disease activity and prognosis. Histology and generic markers of kidney dysfunction, such as proteinuria, hematuria, and estimated glomerular filtration rate, are commonly used to assess kidney damage. Noninvasive biomarkers that can be used to provide diagnostic and prognostic information, enable risk stratification, guide treatment selection, and help monitor treatment response are greatly needed. On the basis of limited data, several promising novel biomarkers specifically related to IgA nephropathy pathophysiology have been proposed and need to be validated and standardized for use in routine clinical care. Once these biomarkers become available, the hope is that they will lead to early diagnosis of IgA nephropathy and provide more accurate prognosis of disease for individual patients. Given the complexity of the pathogenesis of IgA nephropathy, it seems likely that multiple biomarkers will need to be used to optimize patient care.
The International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) was established to aid understanding of the status and capacity of countries to provide optimal kidney care worldwide. This report presents the current characteristics of kidney care in the ISN Newly Independent States (NIS) and Russia region. Although the median prevalence of chronic kidney disease (CKD) was higher (11.4%) than the global median (9.5%), the median CKD-related death rate (1.4%) and prevalence of treated kidney failure (KF) in the region (411 per million population [pmp]) were lower than they are globally (2.5% and 822.8 pmp, respectively). Capacity to provide an adequate frequency of hemodialysis (HD) and kidney transplantation services is present in all the countries (100%). In spite of significant economic advancement, the region has critical shortages of nephrologists, dietitians, transplant coordinators, social workers, palliative care physicians, and kidney supportive care nurses. Home HD remains unavailable in any country in the region. Although national registries for dialysis and kidney transplantation are available in most of the countries across the ISN NIS and Russia region, few registries exist for nondialysis CKD and acute kidney injury. Although a national strategy for improving care for CKD patients is presented in more than half of the countries, no country in the region had a CKD-specific policy. Strategies that incorporate workforce training, planning, and development for all KF caregivers could help ensure sustainable kidney care delivery in the ISN NIS and Russia region. The International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) was established to aid understanding of the status and capacity of countries to provide optimal kidney care worldwide. This report presents the current characteristics of kidney care in the ISN Newly Independent States (NIS) and Russia region. Although the median prevalence of chronic kidney disease (CKD) was higher (11.4%) than the global median (9.5%), the median CKD-related death rate (1.4%) and prevalence of treated kidney failure (KF) in the region (411 per million population [pmp]) were lower than they are globally (2.5% and 822.8 pmp, respectively). Capacity to provide an adequate frequency of hemodialysis (HD) and kidney transplantation services is present in all the countries (100%). In spite of significant economic advancement, the region has critical shortages of nephrologists, dietitians, transplant coordinators, social workers, palliative care physicians, and kidney supportive care nurses. Home HD remains unavailable in any country in the region. Although national registries for dialysis and kidney transplantation are available in most of the countries across the ISN NIS and Russia region, few registries exist for nondialysis CKD and acute kidney injury. Although a national strategy for improving care for CKD patients is presented in more than half of the countries, no country in the region had a CKD-specific policy. Strategies that incorporate workforce training, planning, and development for all KF caregivers could help ensure sustainable kidney care delivery in the ISN NIS and Russia region. Update on variability in organization and structures of kidney care across world regionsKidney International SupplementsVol. 13Issue 1PreviewGlobally, the number of people suffering from kidney disease is approaching 1 billion.1 This estimate is almost twice the number of people living with diabetes mellitus2 in 2021, and more than 20 times the number of people living with the human immunodeficiency virus (HIV) in 2022.3 Kidney disease recently has been ranked among the top-10 leading causes of death worldwide by the World Health Organization (WHO).4 Progression of chronic kidney disease (CKD) to kidney failure is associated with poor outcomes, including loss of life years, catastrophic health expenditures, reduced quality of life, and excess mortality. Full-Text PDF Variations in kidney care management and access: regional assessments of the 2023 International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewWorldwide, substantial evidence shows the rising incidence and prevalence of chronic kidney disease (CKD) and kidney failure requiring dialysis or transplantation.1 Evidence also links CKD and kidney failure with excess morbidity and mortality2 and immense economic challenges3 for families and countries. Nearly a billion people are estimated to be living with kidney disease worldwide.4 CKD, which ranks 12th among global causes of death, accounted for 1.43 million deaths in 2019, a 137% increase from 1990. Full-Text PDF
The International Society of Nephrology (ISN) region of Oceania and South East Asia (OSEA) is a mix of high- and low-income countries, with diversity in population demographics and densities. Three iterations of the ISN-Global Kidney Health Atlas (GKHA) have been conducted, aiming to deliver in-depth assessments of global kidney care across the spectrum from early detection of CKD to treatment of kidney failure. This paper reports the findings of the latest ISN-GKHA in relation to kidney-care capacity in the OSEA region. Among the 30 countries and territories in OSEA, 19 (63%) participated in the ISN-GKHA, representing over 97% of the region's population. The overall prevalence of treated kidney failure in the OSEA region was 1203 per million population (pmp), 45% higher than the global median of 823 pmp. In contrast, kidney replacement therapy (KRT) in the OSEA region was less available than the global median (chronic hemodialysis, 89% OSEA region vs. 98% globally; peritoneal dialysis, 72% vs. 79%; kidney transplantation, 61% vs. 70%). Only 56% of countries could provide access to dialysis to at least half of people with incident kidney failure, lower than the global median of 74% of countries with available dialysis services. Inequalities in access to KRT were present across the OSEA region, with widespread availability and low out-of-pocket costs in high-income countries and limited availability, often coupled with large out-of-pocket costs, in middle- and low-income countries. Workforce limitations were observed across the OSEA region, especially in lower-middle–income countries. Extensive collaborative work within the OSEA region and globally will help close the noted gaps in kidney-care provision. The International Society of Nephrology (ISN) region of Oceania and South East Asia (OSEA) is a mix of high- and low-income countries, with diversity in population demographics and densities. Three iterations of the ISN-Global Kidney Health Atlas (GKHA) have been conducted, aiming to deliver in-depth assessments of global kidney care across the spectrum from early detection of CKD to treatment of kidney failure. This paper reports the findings of the latest ISN-GKHA in relation to kidney-care capacity in the OSEA region. Among the 30 countries and territories in OSEA, 19 (63%) participated in the ISN-GKHA, representing over 97% of the region's population. The overall prevalence of treated kidney failure in the OSEA region was 1203 per million population (pmp), 45% higher than the global median of 823 pmp. In contrast, kidney replacement therapy (KRT) in the OSEA region was less available than the global median (chronic hemodialysis, 89% OSEA region vs. 98% globally; peritoneal dialysis, 72% vs. 79%; kidney transplantation, 61% vs. 70%). Only 56% of countries could provide access to dialysis to at least half of people with incident kidney failure, lower than the global median of 74% of countries with available dialysis services. Inequalities in access to KRT were present across the OSEA region, with widespread availability and low out-of-pocket costs in high-income countries and limited availability, often coupled with large out-of-pocket costs, in middle- and low-income countries. Workforce limitations were observed across the OSEA region, especially in lower-middle–income countries. Extensive collaborative work within the OSEA region and globally will help close the noted gaps in kidney-care provision. Update on variability in organization and structures of kidney care across world regionsKidney International SupplementsVol. 13Issue 1PreviewGlobally, the number of people suffering from kidney disease is approaching 1 billion.1 This estimate is almost twice the number of people living with diabetes mellitus2 in 2021, and more than 20 times the number of people living with the human immunodeficiency virus (HIV) in 2022.3 Kidney disease recently has been ranked among the top-10 leading causes of death worldwide by the World Health Organization (WHO).4 Progression of chronic kidney disease (CKD) to kidney failure is associated with poor outcomes, including loss of life years, catastrophic health expenditures, reduced quality of life, and excess mortality. Full-Text PDF Variations in kidney care management and access: regional assessments of the 2023 International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewWorldwide, substantial evidence shows the rising incidence and prevalence of chronic kidney disease (CKD) and kidney failure requiring dialysis or transplantation.1 Evidence also links CKD and kidney failure with excess morbidity and mortality2 and immense economic challenges3 for families and countries. Nearly a billion people are estimated to be living with kidney disease worldwide.4 CKD, which ranks 12th among global causes of death, accounted for 1.43 million deaths in 2019, a 137% increase from 1990. Full-Text PDF
Worldwide, substantial evidence shows the rising incidence and prevalence of chronic kidney disease (CKD) and kidney failure requiring dialysis or transplantation. 1 GBD Chronic Kidney Disease CollaborationGlobal, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020; 395: 709-733 Abstract Full Text Full Text PDF PubMed Scopus (2952) Google Scholar Evidence also links CKD and kidney failure with excess morbidity and mortality 2 Feng X. Hou N. Chen Z. et al. Secular trends of epidemiologic patterns of chronic kidney disease over three decades: an updated analysis of the Global Burden of Disease Study 2019. BMJ Open. 2023; 13e064540 Crossref Scopus (7) Google Scholar and immense economic challenges 3 Crosby L. Baker P. Hangoma P. et al. Dialysis in Africa: the need for evidence-informed decision making. Lancet Glob Health. 2020; 8: e476-e477 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar for families and countries. Nearly a billion people are estimated to be living with kidney disease worldwide. 4 Jager K.J. Kovesdy C. Langham R. et al. A single number for advocacy and communication—worldwide more than 850 million individuals have kidney diseases. Kidney Int. 2019; 96: 1048-1050 Abstract Full Text Full Text PDF PubMed Google Scholar CKD, which ranks 12th among global causes of death, accounted for 1.43 million deaths in 2019, a 137% increase from 1990. 2 Feng X. Hou N. Chen Z. et al. Secular trends of epidemiologic patterns of chronic kidney disease over three decades: an updated analysis of the Global Burden of Disease Study 2019. BMJ Open. 2023; 13e064540 Crossref Scopus (7) Google Scholar With the rising prevalence of CKD and kidney failure, the cost of coverage for kidney replacement therapy (KRT; including dialysis and kidney transplantation) continues its astronomical rise for health systems, individuals, and families. For instance, although all kidney failure patients accounted for <1% of the Medicare population in the US, they represented >6% of Medicare payments in 2020. 5 US Renal Data SystemAnnual data report: End Stage Renal Disease. Chapter 9: Healthcare expenditures for persons with ESRD. https://usrds-adr.niddk.nih.gov/2022/end-stage-renal-disease/9-healthcare-expenditures-for-persons-with-esrdDate accessed: November 19, 2023 Google Scholar Estimates of the cost of reimbursement for hemodialysis treatment for people with kidney failure in sub-Saharan Africa showed that the total costs would be equivalent to 15%–55% of total domestic governmental health expenditure in 2010. 3 Crosby L. Baker P. Hangoma P. et al. Dialysis in Africa: the need for evidence-informed decision making. Lancet Glob Health. 2020; 8: e476-e477 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Global differences in availability, accessibility, and affordability of KRT across countries have been reported, 6 Bello A.K. Levin A. Lunney M. et al. Status of care for end stage kidney disease in countries and regions worldwide: international cross sectional survey. BMJ. 2019; 367: l5873 Crossref PubMed Scopus (136) Google Scholar and where these are lacking, this leads to poor patient outcomes. 7 Robinson B.M. Akizawa T. Jager K.J. et al. Factors affecting outcomes in patients reaching end-stage kidney disease worldwide: differences in access to renal replacement therapy, modality use, and haemodialysis practices. Lancet. 2016; 388: 294-306 Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar , 8 Liyanage T. Ninomiya T. Jha V. et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet. 2015; 385: 1975-1982 Abstract Full Text Full Text PDF PubMed Scopus (1394) Google Scholar , 9 Ashuntantang G. Osafo C. Olowu W.A. et al. Outcomes in adults and children with end-stage kidney disease requiring dialysis in sub-Saharan Africa: a systematic review. Lancet Glob Health. 2017; 5: e408-e417 Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Capacity for the management of kidney failure in the International Society of Nephrology South Asia region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewThe South Asia region is facing a high burden of chronic kidney disease (CKD) with limited health resources and low expenditure on health care. In addition to the burden of CKD and kidney failure from traditional risk factors, CKD of unknown etiologies from India and Sri Lanka compounds the challenges of optimal management of CKD in the region. From the third edition of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA), we present the status of CKD burden, infrastructure, funding, resources, and health care personnel using the World Health Organization's building blocks for health systems in the ISN South Asia region. Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology Newly Independent States and Russia region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewThe International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) was established to aid understanding of the status and capacity of countries to provide optimal kidney care worldwide. This report presents the current characteristics of kidney care in the ISN Newly Independent States (NIS) and Russia region. Although the median prevalence of chronic kidney disease (CKD) was higher (11.4%) than the global median (9.5%), the median CKD-related death rate (1.4%) and prevalence of treated kidney failure (KF) in the region (411 per million population [pmp]) were lower than they are globally (2.5% and 822.8 pmp, respectively). Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology Middle East region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewThe highest financial and symptom burdens and the lowest health-related quality-of-life scores are seen in people with kidney failure. A total of 11 countries in the International Society of Nephrology (ISN) Middle East region responded to the ISN-Global Kidney Health Atlas. The prevalence of chronic kidney disease (CKD) in the region ranged from 4.9% in Yemen to 12.2% in Lebanon, whereas prevalence of kidney failure treated with dialysis or transplantation ranged from 152 per million population (pmp) in the United Arab Emirates to 869 pmp in Kuwait. Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology Eastern and Central Europe region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewDelivery of care for kidney failure (KF) globally has a significant disparity; even in some countries, it means end of life for the person. The International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) tries to address gaps in KF care and standardize global nephrology care. From the third iteration of the ISN-GKHA, we present data for countries in the ISN Eastern and Central Europe region. The median prevalences of chronic kidney disease (12.8%) and treated KF (873.5 pmp) were higher than the global rates, respectively. Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology Western Europe region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewWestern Europe boasts advanced health care systems, robust kidney care guidelines, and a well-established health care workforce. Despite this, significant disparities in kidney replacement therapy incidence, prevalence, and transplant access exist. This paper presents the third International Society of Nephrology Global Kidney Health Atlas's findings on kidney care availability, accessibility, affordability, and quality in 22 Western European countries, representing 99% of the region's population. Full-Text PDF Update on variability in organization and structures of kidney care across world regionsKidney International SupplementsVol. 13Issue 1PreviewGlobally, the number of people suffering from kidney disease is approaching 1 billion.1 This estimate is almost twice the number of people living with diabetes mellitus2 in 2021, and more than 20 times the number of people living with the human immunodeficiency virus (HIV) in 2022.3 Kidney disease recently has been ranked among the top-10 leading causes of death worldwide by the World Health Organization (WHO).4 Progression of chronic kidney disease (CKD) to kidney failure is associated with poor outcomes, including loss of life years, catastrophic health expenditures, reduced quality of life, and excess mortality. Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology North America and the Caribbean region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewThe International Society of Nephrology Global Kidney Health Atlas charts the availability and capacity of kidney care globally. In the North America and the Caribbean region, the Atlas can identify opportunities for kidney care improvement, particularly in Caribbean countries where structures for systematic data collection are lacking. In this third iteration, respondents from 12 of 18 countries from the region reported a 2-fold higher than global median prevalence of dialysis and transplantation, and a 3-fold higher than global median prevalence of dialysis centers. Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology Oceania and South East Asia (OSEA) region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewThe International Society of Nephrology (ISN) region of Oceania and South East Asia (OSEA) is a mix of high- and low-income countries, with diversity in population demographics and densities. Three iterations of the ISN-Global Kidney Health Atlas (GKHA) have been conducted, aiming to deliver in-depth assessments of global kidney care across the spectrum from early detection of CKD to treatment of kidney failure. This paper reports the findings of the latest ISN-GKHA in relation to kidney-care capacity in the OSEA region. Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology Latin America region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewSuccessful management of chronic kidney disease (CKD) in Latin America (LA) continues to represent a challenge due to high disease burden and geographic disparities and difficulties in terms of capacity, accessibility, equity, and quality of kidney failure care. Although LA has experienced significant social and economic progress over the past decades, there are still important inequities in health care access. Through this third iteration of the International Society of Nephrology Global Kidney Health Atlas, the indicators regarding kidney failure care in LA are updated. Full-Text PDF Capacity for the management of kidney failure in the International Society of Nephrology Africa region: report from the 2023 ISN Global Kidney Atlas (ISN-GKHA)Kidney International SupplementsVol. 13Issue 1PreviewThe burden of chronic kidney disease and associated risk of kidney failure are increasing in Africa. The management of people with chronic kidney disease is fraught with numerous challenges because of limitations in health systems and infrastructures for care delivery. From the third iteration of the International Society of Nephrology Global Kidney Health Atlas, we describe the status of kidney care in the ISN Africa region using the World Health Organization building blocks for health systems. Full-Text PDF
The International Society of Nephrology Global Kidney Health Atlas charts the availability and capacity of kidney care globally. In the North America and the Caribbean region, the Atlas can identify opportunities for kidney care improvement, particularly in Caribbean countries where structures for systematic data collection are lacking. In this third iteration, respondents from 12 of 18 countries from the region reported a 2-fold higher than global median prevalence of dialysis and transplantation, and a 3-fold higher than global median prevalence of dialysis centers. The peritoneal dialysis prevalence was lower than the global median, and transplantation data were missing from 6 of the 10 Caribbean countries. Government-funded payments predominated for dialysis modalities, with greater heterogeneity in transplantation payor mix. Services for chronic kidney disease, such as monitoring of anemia and blood pressure, and diagnostic capability relying on serum creatinine and urinalyses were universally available. Notable exceptions in Caribbean countries included non-calcium-based phosphate binders and kidney biopsy services. Personnel shortages were reported across the region. Kidney failure was identified as a governmental priority more commonly than was chronic kidney disease or acute kidney injury. In this generally affluent region, patients have better access to kidney replacement therapy and chronic kidney disease-related services than in much of the world. Yet clear heterogeneity exists, especially among the Caribbean countries struggling with dialysis and personnel capacity. Important steps to improve kidney care in the region include increased emphasis on preventive care, a focus on home-based modalities and transplantation, and solutions to train and retain specialized allied health professionals.
Globally, the number of people suffering from kidney disease is approaching 1 billion.1 This estimate is almost twice the number of people living with diabetes mellitus2 in 2021, and more than 20 times the number of people living with the human immunodeficiency virus (HIV) in 2022.3 Kidney disease recently has been ranked among the top-10 leading causes of death worldwide by the World Health Organization (WHO).4 Progression of chronic kidney disease (CKD) to kidney failure is associated with poor outcomes, including loss of life years, catastrophic health expenditures, reduced quality of life, and excess mortality.
A large body of evidence implicates the renin-angiotensin system in the pathogenesis of cardiovascular disease. However, not everyone understands that the magnitude of the risk reduction achieved in clinical trials with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is only a fraction of the residual risk for cardiovascular events and death. This paper addresses limitations of current therapeutic approaches based on renin-angiotensin system blockade for hypertension and cardiovascular disease by illustrating the complex biochemical physiology and mechanism of classical and alternate angiotensin peptide formation. Emerging evidence of alternate mechanisms that bypass both renin and angiotensin-converting enzyme to produce the angiotensins in tissues and cells is not currently universally recognized. Currently available treatment would benefit from further insights to help fully meet the aims of patient care, and the challenge is to delve more deeply into the renin-angiotensin system cascade, with the aim of enhancing therapeutics for renin-angiotensin system inhibition. This article provides a reappraisal of the renin-angiotensin-aldosterone cascade, highlighting newly elucidated intermediary components and interplay, and their consequent implications and relevance for understanding the long-term contribution of angiotensin II in cardiovascular diseases and their therapy.
The past 90 years have witnessed an extraordinary trajectory of scientific discovery relating to aldosterone and mineralocorticoid receptor (MR) activation, and a profound reappraisal of their physiological and pathophysiological roles. Although most reviews hark back to 1953 and the isolation of aldosterone by Simpson et al.,1,2 in truth we must revert to an earlier decade for a complete picture. Although many readers will date the birth of the discovery of aldosterone (initially called "electrocortin") to 1953, when Simpson et al.
Chronic kidney disease (CKD) in type 2 diabetes is a large and growing problem leading to end-stage kidney disease, atherosclerotic cardiovascular disease, and heart failure (HF). Aldosterone is a key risk factor in promoting inflammation and fibrosis, which causes cardiorenal failure. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers does not prevent overactivation of the mineralocorticoid receptor. Therapeutic options and challenges with blocking MR overactivation by aldosterone are reviewed herein. Whereas classic steroidal mineralocorticoid receptor antagonists (MRAs) reduced albuminuria in short-term studies of diabetic and nondiabetic CKD, long-term studies evaluating hard endpoints such as loss of kidney function were not conducted in CKD because of side effects (primarily hyperkalemia). Novel nonsteroidal MRAs reduce proteinuria and markers of HF, with lower risk of hyperkalemia and without renal impairment, in comparison to steroidal MRAs. Furthermore, recent clinical trials have demonstrated the efficacy of the novel, selective, nonsteroidal MRA finerenone to delay progression of kidney and cardiovascular disease, including HF, in patients with CKD and type 2 diabetes. Concomitantly, the safety profile of finerenone is good, with few patients discontinuing treatment because of hyperkalemia, even among study participants with a low estimated glomerular filtration rate (>25 ml/min per 1.73 m2). Novel nonsteroidal attractive addition to the treatment paradigm in the management of patients with CKD and type 2 diabetes, overactivation.
Aldosterone controls salt-water homeostasis by acting on the mineralocorticoid receptor (MR), a ligand-activated transcription factor, in kidney epithelial cells. However, it is now evident that the MR is expressed in multiple cell types and tissues, acting as a key driver of cardiovascular disease. MR antagonists have proven to be highly efficient in patients with heart failure and reduced ejection fraction, and they are a cornerstone of contemporary therapy. In the past decade, a series of experimental studies using models with cell type-specific MRs uncovered the cellular and molecular mechanisms underlying its detrimental effect on left ventricular remodeling. Based on these findings, the potential of MR antagonists has been evaluated in other cardiovascular diseases, including coronary artery disease, arterial hypertension, heart failure with preserved ejection fraction, pulmonary hypertension, atrial fibrillation, and heart valve disease. The present review summarizes the current knowledge on MR activation and antagonism in cardiovascular disease.
The recent successful demonstrations that the nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone provides effective kidney and cardiovascular (CV) protection in patients with chronic kidney disease (CKD) and type 2 diabetes constitutes a platform for considering and implementing an array of future clinical trials in patients with nondiabetic CKD. Activation of the MR, with consequent inflammation and fibrosis, should be operative as a pathogenetic mediator not only in patients with diabetic CKD but also in those with nondiabetic kidney disease. Consequently, it is proposed that MR antagonism therapy will be equally efficacious in patients with nondiabetic CKD. Recently, a major new clinical trial has been initiated testing finerenone in patients with nondiabetic kidney disease (FIND-CKD; NCT05047263). A second clinical development program, FIONA, is dedicated to studies of finerenone in children with glomerular and nonglomerular CKD. Finally, the interrelationship of fibroblast growth factor 23 (FGF23), membrane αKlotho (hereafter called Klotho), and aldosterone may be a propitious subject for future investigation. The interplay and intersection of these seemingly disparate yet intricate relationships may unmask novel, and indeed compelling, opportunities for therapeutic interventions that are capable of interrupting the vicious cycle of excess aldosterone/MR activation and FGF23 secretion with concomitant Klotho insufficiency characteristically present in patients with CKD.
Chronic kidney disease is a major global health challenge, and mineralocorticoid receptor (MR) signaling is thought to play a role in disease progression. The classic role of the MR is the regulation of fluid and electrolyte homeostasis via differential gene expression, and recently its role in modulating inflammation and fibrosis has been identified. In addition to expression of the MR in renal epithelial cells, it is also found in nonepithelial cells, such as endothelial cells, vascular smooth muscle cells, podocytes, and fibroblasts. Targeting the MR in these cells may play a role in offering protection against inflammation and fibrosis in the kidneys and the cardiovascular system. Herein, data from preclinical cell-specific MR knockout mouse models and in vitro studies that help uncover the role of the MR in nonepithelial cells are presented. This review also discusses several potential targets that offer opportunities for the targeting of MR signaling in nonepithelial cells.
Chronic kidney disease is a progressive condition that affects >10% of the general population worldwide, amounting to >800 million individuals. Chronic kidney disease is more prevalent in older individuals, women, racial minorities, and in people experiencing diabetes mellitus and hypertension. Chronic kidney disease represents an especially large burden in low- and middleincome countries, which are least equipped to deal with its consequences. Chronic kidney disease has emerged as one of the leading causes of mortality worldwide, and it is one of a small number of non-communicable diseases that have shown an increase in associated deaths over the past 2 decades. The high number of affected individuals and the significant adverse impact of chronic kidney disease should prompt enhanced efforts for better prevention and treatment.
Chronic kidney disease is characterized by progressive scarring that results in loss of normal tissue in the kidney and eventually end-stage kidney disease. Interstitial fibrosis and tubular atrophy have been most closely correlated with decline in renal function. Potential mechanisms include profibrotic changes in tubules, influx of profibrotic rather than healing reparative macrophages, and an increase in activated myofibroblasts. Aldosterone activates the mineralocorticoid receptor in the collecting duct to increase sodium reabsorption, resulting in increased blood pressure. Aldosterone also promotes inflammation and fibrosis in the kidney by activating the mineralocorticoid receptor in other cellular compartments, including podocytes, mesangial cells, epithelial cells, and myeloid cells. Aldosterone also may act indirectly by stimulating factors in epithelial tissues that contribute to inflammatory macrophage polarization, myofibroblast differentiation, and progressive fibrosis. This review discusses the potential mechanisms by which aldosterone and mineralocorticoid receptor activation promotes inflammation and fibrosis via nonclassical pathways in the kidney.
